In the proposed study we will investigate soluble immunologic factors present in serum following transfusion transmission through the course of acute HCV infection to identify biomarkers influencing and predicting spontaneous HCV clearance versus chronic HCV infection. TTVS is a rare cohort with a large number of serial serum samples spanning a year following acute HCV infection with well characterized clinical parameters including clear categorization of disease outcome status. These samples and predicate data will allow us to effectively examine the specific aims outlined below. The proposed research will demonstrate the importance of donor and recipient sample collection and retention. The research will also show how the ongoing use of biorepositories created and maintained by NHLBI can afford continuing value by improving our understanding of Hepatitis C virus biology greater than thirty years after the TTVS repository was developed. We have generated preliminary results from sixteen TTVS subjects and observed changes in expression kinetics of IP- 10, TNF-? and IL-10 during acute HCV infection in both HCV resolvers and chronic HCV infections, albeit different expression kinetics in the two groups. We observed elevation in soluble IL-2Ra expression only in spontaneous HCV resolvers compared to chronic HCV or uninfected controls. In Specific Aim1, we will determine IP-10, TNF-??, IL-10, sIL-2Ra and TGF-?? expression kinetics in sera during acute HCV infection following transfusion transmission in the full cohort of 94 infected TTVS recipients. In Specific Aim 2, we will determine IL-18 and/or IL-28B protein expression as a biomarker of spontaneous HCV resolution in transfusion transmitted HCV infection. Based on recent groundbreaking findings, we will also determine whether IL-18 and IL-28B genetic polymorphisms correlate with spontaneous HCV resolution in the TTVS cohort. Given the extent of individual suffering and the overall impact to public health as a result of HCV infection, there is a high priority for continue research into HCV prevention, prognosis and clinical management. The examination of immune correlates with clinical outcome in a cohort of Acute Hepatitis C virus infection such as TTVS will advance our capacity to combat and treat HCV.